The present invention relates to prepolymers useful in the manufacture of biocompatible medical devices. More particularly, the present invention relates to aromatic-substituted polysiloxane prepolymers capable of copolymerization with one or more other monomers to form polymeric compositions having desirable physical characteristics and refractive indices for use in the manufacture of ophthalmic implants.
Since the 1940""s optical devices in the form of intraocular lens (IOL) implants have been utilized as replacements for diseased or damaged natural ocular lenses. In most cases, an intraocular lens is implanted within an eye at the time of surgically removing the diseased or damaged natural lens, such as for example, in the case of cataracts. For decades, the preferred material for fabricating such intraocular lens implants was poly(methyl methacrylate), which is a rigid, glassy polymer.
Softer, more flexible IOL implants have gained in popularity in more recent years due to their ability to be compressed, folded, rolled or otherwise deformed. Such softer IOL implants may be deformed prior to insertion thereof through an incision in the cornea of an eye. Following insertion of the IOL in an eye, the IOL returns to its original pre-deformed shape due to the memory characteristics of the soft material. Softer, more flexible IOL implants as just described may be implanted into an eye through an incision that is much smaller, i.e., less than 4.0 mm, than that necessary for more rigid IOLs, i.e., 5.5 to 7.0 mm. A larger incision is necessary for more rigid IOL implants because the lens must be inserted through an incision in the cornea slightly larger than the diameter of the inflexible IOL optic portion. Accordingly, more rigid IOL implants have become less popular in the market since larger incisions have been found to be associated with an increased incidence of postoperative complications, such as induced astigmatism.
With recent advances in small-incision cataract surgery, increased emphasis has been placed on developing soft, foldable materials suitable for use in artificial IOL implants. In general, the materials of current commercial IOLs fall into one of three categories: silicones, hydrophilic acrylics and hydrophobic acrylics.
In general, high water content hydrophilic acrylics, or xe2x80x9chydrogels,xe2x80x9d have relatively low refractive indices, making them less desirable than other materials with respect to minimal incision size. Low refractive index materials require a thicker IOL optic portion to achieve a given refractive power. Silicone materials may have higher refractive indices than high-water content hydrogels, but tend to unfold explosively after being placed in the eye in a folded position. Explosive unfolding can potentially damage the corneal endothelium and/or rupture the natural lens capsule and associated zonules. Low glass transition temperature hydrophobic acrylic materials are desirable because they typically have a high refractive index and unfold more slowly and more controllably than silicone materials. Unfortunately, low glass transition temperature hydrophobic acrylic materials, which contain little or no water initially, may absorb pockets of water in vivo causing light reflections or xe2x80x9cglistenings.xe2x80x9d Furthermore, it may be difficult to achieve ideal folding and unfolding characteristics due to the temperature sensitivity of some acrylic polymers.
Because of the noted shortcomings of current polymeric materials available for use in the manufacture of ophthalmic devices, there is a need for stable, biocompatible polymeric materials having desirable physical characteristics and refractive indices.
Soft, foldable, high refractive index, high elongation, polymeric compositions of the present invention are synthesized through the copolymerization of aromatic-substituted polysiloxane prepolymers with one or more aromatic monomers, alkyl monomers, hydrophilic monomers or a combination thereof. Production processes of the present invention using the subject aromatic-substituted polysiloxane prepolymers, produce materials having desirable physical properties for use in the manufacture of ophthalmic devices. The polymeric compositions of the present invention are transparent and have relatively high strength for durability during surgical manipulation, relatively high elongation and relatively high refractive index. The subject polymeric compositions are particularly well suited for use in the manufacture of ophthalmic devices such as intraocular lens (IOL) implants, contact lenses, keratoprostheses, corneal rings, corneal inlays and the like.
Preferred aromatic-substituted polysiloxane prepolymers for use in the production of the polymeric compositions of present invention have a structure generally represented by Formula 1 below, which may be produced from precursors having a structure generally represented by Formula 2 below: 
wherein the V groups may be the same or different unsaturated photo or thermal polymerizable substituents of the general structure R3CHxe2x95x90C(R4)(CH2)p(W)q(Z)q(Ar)qR5; the R groups may be the same or different saturated C1-10 hydrocarbon substituents; the R1 groups may be the same or different alkyl substituents; the R2 groups may be the same or different alkyl substituents, fluoroalkyl substituents or alkyl-fluoroalkyl substituents with ether linkages therebetween, or the same or different aromatic substituents; the L groups, which may or may not be present in the subject prepolymers, may be the same or different urethane, urea, carbonate or ester linkages; y is a natural number greater than 4 representing the sum of siloxane moieties with randomly differing R2 groups as defined above with a molar ratio of aromatic substituents to alkyl substituents no less than 1:4; x is a natural number such that the prepolymer molecular weight is at least approximately 1000 and refractive index is at least approximately 1.45 or greater; m is a natural number greater than 4 representing the sum of siloxane moieties with randomly differing R2 groups as defined above with a molar ratio of aromatic substituents to alkyl substituents no less than 1:4 such that the prepolymer molecular weight is at least approximately 1000 and refractive index is at least approximately 1.45 or greater; R3 is selected from the group consisting of hydrogen, C1-10 alkyl and xe2x80x94COxe2x80x94Uxe2x80x94R1; R4 is selected from the group consisting of hydrogen and methyl; R5 is a C1-10 divalent alkylene radical; the W group is selected from the group consisting of xe2x80x94COxe2x80x94 and xe2x80x94OCOxe2x80x94; the Z group is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94NHxe2x80x94; the Z1 groups may be the same or different selected from the group consisting of xe2x80x94OH and xe2x80x94NH2; the Ar groups may be the same or different C6-30 aromatic radicals; p is a non-negative integer less than 7; q is either 0 or 1; and U is selected from the group consisting of xe2x80x94OC1-12 alkyl radical, xe2x80x94SC1-12 alkyl radical and xe2x80x94NHC1-12 alkyl radical.
Accordingly, it is an object of the present invention to provide transparent, biocompatible polymeric compositions having desirable physical characteristics and relatively high refractive indices.
Another object of the present invention is to provide polymeric compositions having relatively high refractive indices and good clarity.
Another object of the present invention is to provide polymeric compositions suitable for use in the manufacture of ophthalmic devices.
Another object of the present invention is to provide polymeric compositions suitable for use in the manufacture of intraocular lens implants.
Still another object of the present invention is to provide polymeric compositions that are economical to produce.
These and other objectives and advantages of the present invention, some of which are specifically described and others that are not, will become apparent from the detailed description and claims that follow.
The present invention relates to novel aromatic-substituted polysiloxane prepolymers and the use of such prepolymers to produce biocompatible polymeric compositions having desirable physical properties and relatively high refractive indices for use in the manufacture of ophthalmic devices. The aromatic-substituted polysiloxane prepolymers of the present invention are represented generally by Formula 1 below which are produced from precursors represented generally by Formula 2 below: 
wherein the V groups may be the same or different unsaturated photo or thermal polymerizable substituents of the general structure R3CHxe2x95x90C(R4)(CH2)p(W)q(Z)q(Ar)qR5; the R groups may be the same or different saturated C1-10 hydrocarbon substituents such as for example but not limited to methyl, propyl, octyl, trimethylene or tetramethylene but preferably methyl for increased stability; the R1 groups may be the same or different C1-10 alkyl substituents such as for example but not limited to methyl, propyl, or octyl but preferably methyl for increased stability; the R2 groups may be the same or different selected from the group consisting of C1-10 alkyl substituents such as for example but not limited to methyl, propyl or octyl but preferably methyl for increased stability, C1-10fluoroalkyl substituents such as for example but not limited to fluoromethyl, fluoropropyl or fluorooctyl but preferably fluoromethyl for increased stability, C2-20 alkyl-fluoroalkyl substituents, which may or may not have ether linkages between the alkyl and fluoroalkyl substituents, such as for example but not limited to methyl-fluoromethyl, propyl-fluorobutyl or octyl-fluoropentyl but preferably methyl-fluoromethyl for increased stability, and C6-30 aromatic substituents such as for example but not limited to phenyl or naphthyl; the L groups, which may or may not be present in the subject prepolymers, may be the same or different urethane, urea, carbonate or ester linkages such as for example but not limited to T, Txe2x80x94R6xe2x80x94T or Txe2x80x94R6xe2x80x94Txe2x80x94R7xe2x80x94Txe2x80x94R6xe2x80x94T; y is a natural number greater than 4 representing the sum of siloxane moieties with randomly differing R2 groups as defined above so as to have a molar ratio of aromatic substituents to alkyl substituents no less than 1:4; x is a natural number such that the prepolymer molecular weight is at least approximately 1000 and refractive index is at least approximately 1.45; m is a natural number greater than 4 representing the sum of siloxane moieties with randomly differing R2 groups as defined above with a molar ratio of aromatic substituents to alkyl substituents no less than 1:4 such that the prepolymer molecular weight is at least approximately 1000 and refractive index is at least approximately 1.45 or greater; R3 is selected from the group consisting of hydrogen, C1-10 alkyl such as for example but not limited to methyl, propyl or octyl and xe2x80x94COxe2x80x94Uxe2x80x94R1, but preferably hydrogen; R4 is selected from the group consisting of hydrogen and methyl; R5 is a C1-10 divalent alkylene radical such as for example but not limited to methylene or butylene but preferably methylene; the W group is selected from the group consisting of xe2x80x94COxe2x80x94 and xe2x80x94OCOxe2x80x94; the Z group is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94NHxe2x80x94; the Z1 groups may be the same or different selected from the group consisting of xe2x80x94OH and xe2x80x94NH2; the Ar groups may be the same or different C6-30 aromatic radicals such as for example but not limited to radicals of benzene, naphthalene or phenanthrene; p is a non-negative integer less than 7; q is either 0 or 1; the T groups may be the same or different selected from the group consisting of xe2x80x94OCONHxe2x80x94, xe2x80x94NHCOOxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94OCOOxe2x80x94, xe2x80x94OCOxe2x80x94 and xe2x80x94COOxe2x80x94; R6 is a residue of diisocyanate after removing isocyanate groups; R7 is a residue of diol after removing xe2x80x94OH groups; and U is selected from the group consisting of xe2x80x94OC1-12 alkyl radical, xe2x80x94SC1-12 alkyl radical and xe2x80x94NHC1-12 alkyl radical.
Many xcex1,xcfx89-bis-hydroxyalkyl polysiloxanes or xcex1,xcfx89-bis-aminoalkyl polysiloxanes with varying numbers of aromatic units such as those represented by the structure of Formula 2 are useful in making prepolymers of the present invention. The desired number of aromatic units, such as for example phenyl groups, and the desired prepolymer molecular weight can be produced by reacting 1,3-bis-hydroxyalkyl tetramethyldisiloxane or 1,3-bis-aminoalkyl tetramethyldisiloxane with different combinations of dimethyldimethoxysilane, diphenydimethoxysilane and methylphenyldimethoxysilane at molar ratios of choice. Alternatively, the same prepolymers may be prepared by the same method using cyclic siloxanes with different levels of phenyl groups, such as 1,3,5-trimethyl-1,3,5-triphenylcyclotrisiloxane, 1,1,3,3,5,5-hexamethylcyclotrisiloxane, 1,1,3,3,5,5-hexaphenylcyclotrisiloxane, rather than using silanes as mentioned above. Some examples of polysiloxane precursors so prepared, not intended to be limiting, are xcex1,xcfx89-bis-hydroxybutylpoly(methylphenylsiloxane) (HBPMPS) represented by Formula 3 below, 
wherein the Ph groups may be the same or different C6-30 aromatic substituents such as for example but not limited to phenyl; and x is the same as that defined above for Formula 1; and xcex1,xcfx89-bis-hydroxybutylpoly(methylphenylsiloxane-co-dimethylsiloxane) (HBPMPS-co-DMS) represented by Formula 4 below, 
wherein the Ph groups and x are the same as defined above for Formula 3.
Prepolymers of the present invention are also produced using hydroxyalkyl-terminated polysiloxane precursors with aromatic units such as for example HBPMPS of Formula 3 above. One example of such prepolymers, not intended to be limiting, is derived from isophorone diisocyanate and xcex1,xcfx89-bis-hydroxybutylpoly(methylphenylsiloxane) (HBPMPS), end-capped with 2-hydroxyethylmethacylate as represented by Formula 5 below, 
wherein IPDI represents the residue after removing the isocyanate group, and the Ph groups and x are the same as defined above for Formula 3. The prepolymer represented by Formula 5 has three blocks of IPDI and two blocks of HBPMPS repeating units, commonly referred to as a xe2x80x9cdiblockxe2x80x9d prepolymer. Other prepolymers of similar structure can be prepared by the same method using a hydroxyalkyl-terminated polysiloxane with aromatic units having a molecular weight of choice, and a diisocyanate, a diacid chloride or phosgene in a selected molar ratio and end-capped with a hydroxy or amino containing monomer such as for example 2-hydroxyethyl methacrylate.
Soft, foldable, relatively high refractive index of approximately 1.45 or greater, relatively high elongation of approximately 100 percent or greater polymeric compositions of the present invention are synthesized through the copolymerization of one or more of the subject aromatic-substituted polysiloxane prepolymers with one or more aromatic monomers, alkyl monomers, hydrophilic monomers or a combination thereof.
Examples of aromatic monomers useful in the production of polymeric compositions of the present invention include for example but are not limited to acrylate, methacrylate, acrylamide and methacrylamide, each with C6-30 aromatic substituents. More specific examples of such aromatic monomers include but are not limited to phenyl acrylate, phenyl(meth)acrylate, phenyl acrylamide, benzyl acrylate, benzyl acrylamide, phenylethylacrylate, phenyl(meth)acrylamide, phenylethyl(meth)acrylate and benzyl(meth)acrylate.
Examples of alkyl monomers useful in the production of polymeric compositions of the present invention include for example but are not limited to C1-20 alkyl acrylate, C1-20 alkyl methacrylate, C5-20 acrylamide and C5-20 methacrylamide. More specific examples of such alkyl monomers include for example but are not limited to methyl acrylate, ethyl acrylate, n-propyl acrylate, n-butyl acrylate, n-hexyl acrylate, n-octyl acrylate, 2-ethylhexyl acrylate, n-propyl methacrylate, n-butyl methacrylate, n-hexyl methacrylate, n-octyl methacrylate, 2-ethylhexyl methacrylate and n-octyl acrylamide.
Examples of hydrophilic monomers useful in the production of polymeric compositions of the present invention include for example but are not limited to N,N-dimethyl acrylamide, N-vinylpyrrolidone, 2-hydroxyethyl methacrylate (HEMA), glycerol methacrylate, 2-hydroxyethyl acrylate, acrylamide, n-methyl acrylamide, acrylic acid and (meth)acrylic acid.
The polymeric compositions of the present invention have relatively high refractive indexes of approximately 1.45 or greater, relatively low glass transition temperatures of approximately 30 degrees Celsius or less and relatively high elongation of approximately 100 percent or greater. The polymeric compositions of the present invention with the desirable physical properties noted herein are particularly useful in the manufacture of ophthalmic devices such as but not limited to intraocular lenses (IOLs) and corneal inlays. Examples of polymeric compositions having the above mentioned physical characteristics include those derived from the prepolymer of Formula 5, benzyl acrylate, benzyl methacrylate and dimethylacrylamide (DMA) at different weight ratios. These polymeric materials are either xerogels or hydrogels with up to twenty percent water content by weight per volume (W/V).
IOLs having thin optic portions are critical in enabling a surgeon to minimize surgical incision size. Keeping the surgical incision size to a minimum reduces intraoperative trauma and postoperative complications. A thin IOL optic portion is also critical for accommodating certain anatomical locations in the eye such as the anterior chamber and the ciliary sulcus. IOLs may be placed in the anterior chamber for increasing visual acuity in both aphakic and phakic eyes and placed in the ciliary sulcus for increasing visual acuity in phakic eyes.
The preferred polymeric compositions of the present invention have the flexibility required to allow ophthalmic devices manufactured from the same to be folded or deformed for insertion into an eye through the smallest possible surgical incision, i.e., 3.5 mm or smaller. It is unexpected that the subject polymeric compositions described herein could possess the ideal physical properties disclosed herein. The ideal physical properties of the subject polymeric compositions are unexpected because high refractive index monomers or copolymers typically lend to polymers that have increased crystallinity and decreased clarity, which does not hold true in the case of the subject polymeric compositions.
One or more suitable ultraviolet light absorbers may optionally be used in the manufacture of the subject compositions. Such ultraviolet light absorbers include for example but are not limited to xcex2-(4-benzotriazoyl-3-hydroxyphenoxy) ethyl acrylate, 4-(2-acryloxyethoxy)-2-hydroxybenzophenone, 4-methacryloxy-2-hydroxybenzophenone, 2-(2xe2x80x2-methacryloxy-5xe2x80x2-methylphenyl)benzotriazole, 2-(2xe2x80x2-hydroxy-5xe2x80x2-methacryoxyethylphenyl)-2H-benzotriazole, 2-[3xe2x80x2-tert-butyl-2xe2x80x2-hydroxy-5xe2x80x2-(3xe2x80x3-methacryloyloxypropyl)phenyl]-5-chlorobenzotriazole, 2-[3xe2x80x2-tert-butyl-5xe2x80x2-(3xe2x80x3-dimethylvinylsilylpropoxy)-2xe2x80x2-hydroxyphenyl]-5-methoxybenzotriazole, 2-(3xe2x80x2-allyl-2xe2x80x2-hydroxy-5xe2x80x2-methylphenyl)benzotriazole, 2-[3xe2x80x2-tert-butyl-2xe2x80x2-hydroxy-5xe2x80x2-(3xe2x80x3-methacryloyloxypropoxy)phenyl]-5-methoxybenzotriazole, and 2-[3xe2x80x2-tert-butyl-2xe2x80x2-hydroxy-5xe2x80x2-(3xe2x80x3-methacryloyloxypropoxy)phenyl]-5-chlorobenzotriazole wherein xcex2-(4-benzotriazoyl-3-hydroxyphenoxy)ethyl acrylate is the preferred ultraviolet light absorber due to its effectiveness and availability.